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AI predicts how patients with viral infections, including COVID-19, will fare

Gene expression patterns associated with pandemic viral infections provide a map to help define patients’ immune responses, measure disease severity, predict outcomes and test therapies — for current and future pandemics Credit: UC San Diego Health…

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Gene expression patterns associated with pandemic viral infections provide a map to help define patients’ immune responses, measure disease severity, predict outcomes and test therapies — for current and future pandemics

Credit: UC San Diego Health Sciences

Researchers at University of California San Diego School of Medicine used an artificial intelligence (AI) algorithm to sift through terabytes of gene expression data — which genes are “on” or “off” during infection — to look for shared patterns in patients with past pandemic viral infections, including SARS, MERS and swine flu.

Two telltale signatures emerged from the study, published June 11, 2021 in eBiomedicine. One, a set of 166 genes, reveals how the human immune system responds to viral infections. A second set of 20 signature genes predicts the severity of a patient’s disease. For example, the need to hospitalize or use a mechanical ventilator. The algorithm’s utility was validated using lung tissues collected at autopsies from deceased patients with COVID-19 and animal models of the infection.

“These viral pandemic-associated signatures tell us how a person’s immune system responds to a viral infection and how severe it might get, and that gives us a map for this and future pandemics,” said Pradipta Ghosh, MD, professor of cellular and molecular medicine at UC San Diego School of Medicine and Moores Cancer Center.

Ghosh co-led the study with Debashis Sahoo, PhD, assistant professor of pediatrics at UC San Diego School of Medicine and of computer science and engineering at Jacobs School of Engineering, and Soumita Das, PhD, associate professor of pathology at UC San Diego School of Medicine.

During a viral infection, the immune system releases small proteins called cytokines into the blood. These proteins guide immune cells to the site of infection to help get rid of the infection. Sometimes, though, the body releases too many cytokines, creating a runaway immune system that attacks its own healthy tissue. This mishap, known as a cytokine storm, is believed to be one of the reasons some virally infected patients, including some with the common flu, succumb to the infection while others do not.

But the nature, extent and source of fatal cytokine storms, who is at greatest risk and how it might best be treated have long been unclear.

“When the COVID-19 pandemic began, I wanted to use my computer science background to find something that all viral pandemics have in common — some universal truth we could use as a guide as we try to make sense of a novel virus,” Sahoo said. “This coronavirus may be new to us, but there are only so many ways our bodies can respond to an infection.”

The data used to test and train the algorithm came from publicly available sources of patient gene expression data — all the RNA transcribed from patients’ genes and detected in tissue or blood samples. Each time a new set of data from patients with COVID-19 became available, the team tested it in their model. They saw the same signature gene expression patterns every time.

“In other words, this was what we call a prospective study, in which participants were enrolled into the study as they developed the disease and we used the gene signatures we found to navigate the uncharted territory of a completely new disease,” Sahoo said.

By examining the source and function of those genes in the first signature gene set, the study also revealed the source of cytokine storms: the cells lining lung airways and white blood cells known as macrophages and T cells. In addition, the results illuminated the consequences of the storm: damage to those same lung airway cells and natural killer cells, a specialized immune cell that kills virus-infected cells.

“We could see and show the world that the alveolar cells in our lungs that are normally designed to allow gas exchange and oxygenation of our blood, are one of the major sources of the cytokine storm, and hence, serve as the eye of the cytokine storm,” Das said. “Next, our HUMANOID Center team is modeling human lungs in the context of COVID-19 infection in order to examine both acute and post-COVID-19 effects.”

The researchers think the information might also help guide treatment approaches for patients experiencing a cytokine storm by providing cellular targets and benchmarks to measure improvement.

To test their theory, the team pre-treated rodents with either a precursor version of Molnupiravir, a drug currently being tested in clinical trials for the treatment of COVID-19 patients, or SARS-CoV-2-neutralizing antibodies. After exposure to SARS-CoV-2, the lung cells of control-treated rodents showed the pandemic-associated 166- and 20-gene expression signatures. The treated rodents did not, suggesting that the treatments were effective in blunting cytokine storm.

“It is not a matter of if, but when the next pandemic will emerge,” said Ghosh, who is also director of the Institute for Network Medicine and executive director of the HUMANOID Center of Research Excellence at UC San Diego School of Medicine. “We are building tools that are relevant not just for today’s pandemic, but for the next one around the corner.”

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Co-authors of the study include: Gajanan D. Katkar, Soni Khandelwal, Mahdi Behroozikhah, Amanraj Claire, Vanessa Castillo, Courtney Tindle, MacKenzie Fuller, Sahar Taheri, Stephen A. Rawlings, Victor Pretorius, David M. Smith, Jason Duran, UC San Diego; Thomas F. Rogers, Scripps Research and UC San Diego; Nathan Beutler, Dennis R. Burton, Scripps Research; Sydney I. Ramirez, La Jolla Institute for Immunology; Laura E. Crotty Alexander, VA San Diego Healthcare System and UC San Diego; Shane Crotty, Jennifer M. Dan, La Jolla Institute for Immunology and UC San Diego.

Media Contact
Heather Buschman, PhD
hbuschman@ucsd.edu

Related Journal Article

http://dx.doi.org/10.1016/j.ebiom.2021.103390

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Spread & Containment

AstraZeneca antibody cocktail fails to prevent Covid-19 symptoms in large trial

AstraZeneca said a late-stage trial failed to provide evidence that the company’s Covid-19 antibody therapy protected people who had contact with an infected person from the disease, a small setback in its efforts to find alternatives to vaccines.

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Astra antibody cocktail fails to prevent COVID-19 symptoms in large trial

(Reuters; )

June 15 (Reuters) – AstraZeneca (AZN.L) said on Tuesday a late-stage trial failed to provide evidence that its COVID-19 antibody therapy protected people who had contact with an infected person from the disease, a small setback in its efforts to find alternatives to vaccines.

The study assessed whether the therapy, a cocktail of two types of antibodies, could prevent adults who had been exposed to the virus in the past eight days from developing COVID-19 symptoms.

The therapy, AZD7442, was 33% effective in reducing the risk of people developing symptoms compared with a placebo, but that result was not statistically significant — meaning it might have been due to chance and not the therapy.

The Phase III study, which has not been peer reviewed, included 1,121 participants in the United Kingdom and the United States. The vast majority, though not all, were free of the virus at the start of the trial.

Results for a subset of participants who were not infected to begin with was more encouraging but the primary analysis rested on results from all participants.

FILE PHOTO: A computer image created by Nexu Science Communication together with Trinity College in Dublin, shows a model structurally representative of a betacoronavirus which is the type of virus linked to COVID-19, better known as the coronavirus linked to the Wuhan outbreak, shared with Reuters on February 18, 2020. NEXU Science Communication/via REUTERS

“While this trial did not meet the primary endpoint against symptomatic illness, we are encouraged by the protection seen in the PCR negative participants following treatment with AZD7442,” AstraZeneca Executive Vice President Mene Pangalos said in a statement.

The company is banking on further studies to revive the product’s fortunes. Five more trials are ongoing, testing the antibody cocktail as treatment or in prevention.

The next one will likely be from a larger trial testing the product in people with a weakened immune system due to cancer or an organ transplant, who may not benefit from a vaccine.

TARGETED ALTERNATIVES

AZD7442 belongs to a class of drugs called monoclonal antibodies which mimic natural antibodies produced by the body to fight off infections.

Similar therapies developed by rivals Regeneron (REGN.O) and Eli Lilly (LLY.N) have been approved by U.S. regulators for treating unhospitalised COVID patients.

European regulators have also authorised Regeneron’s therapy and are reviewing those developed by partners GlaxoSmithKline (GSK.L) and Vir Biotechnology (VIR.O) as well as by Lilly and Celltrion (068270.KS).

Regeneron is also seeking U.S. authorisation for its therapy as a preventative treatment.

But the AstraZeneca results are a small blow for the drug industry as it tries to find more targeted alternatives to COVID-19 inoculations, particularly for people who may not be able to get vaccinated or those who may have an inadequate response to inoculations.

The Anglo-Swedish drugmaker, which has faced a rollercoaster of challenges with the rollout of its COVID-19 vaccine, is also developing new treatments and repurposing existing drugs to fight the virus.

AstraZeneca also said on Tuesday it was in talks with the U.S. government on “next steps” regarding a $205 million deal to supply up to 500,000 doses of AZD7442. Swiss manufacturer Lonza (LONN.S) was contracted to produce AZD7442.

Shares in the company were largely unchanged on the London Stock Exchange.

The full results will be submitted for publication in a peer-reviewed medical journal, the company said.

Reporting by Vishwadha Chander in Bengaluru; Editing by Shounak Dasgupta

Our Standards: The Thomson Reuters Trust Principles.

 

Reuters source:

https://www.reuters.com/business/healthcare-pharmaceuticals/astrazeneca-says-its-antibody-treatment-failed-in-preventing-covid-19-exposed-2021-06-15

 

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Government

Former FDA Head Takes on Exec Role at Flagship’s Preemptive Health Initiative

Stephen Hahn, the Commissioner of the U.S. Food and Drug Administration under former President Donald Trump, took on a new role as chief medical officer of a new health security initiative launched by Flagship Pioneering, a life sciences venture firm…

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Former FDA Head Takes on Exec Role at Flagship’s Preemptive Health Initiative

 

Stephen Hahn, the Commissioner of the U.S. Food and Drug Administration (FDA) under former President Donald Trump, has taken on a new role as chief medical officer of a new health security initiative launched by Flagship Pioneering, a life sciences venture firm that incubates and curates biopharma companies.

First announced Monday, Flagship’s Preemptive Medicine and Health Security initiative aimed at developing products that can help people before they get sick. This division will focus on infectious disease threats and pursue bold treatments for existing diseases, including cancer, obesity, and neurodegeneration. 

In a brief statement, Hahn, who served as commissioner from December 2019 until January 2021, said the importance of investing in innovation and preemptive medications has never been more apparent. 

“In my career I have been a doctor and a researcher foremost and it is an honor to join Flagship Pioneering in its efforts to prioritize innovation, particularly in its Preemptive Medicine and Health Security Initiative. The more we can embrace a “what if …” approach the better we can support and protect the health and well-being of people here in the U.S. and around the world,” Hahn said in a statement. 

During his time at the FDA, Hahn was at the forefront of the government’s effort to battle the COVID-19 pandemic. His office oversaw the regulatory authorization of antivirals, antibody therapeutics and vaccines, as well as diagnostics and other tools to battle the novel coronavirus. 

Kevin Dietsch-Pool/Getty Images

Hahn bore the brunt of verbal barbs aimed at the FDA by the former president for not rushing to authorize a vaccine for COVID-19 ahead of the November 2020 election. The second vaccine authorized by the FDA for COVID-19 was developed by Moderna, a Flagship company. 

Prior to his confirmation as FDA Commissioner, Hahn, a well-respected oncologist, served as chief medical executive of the vaunted The University of Texas MD Anderson Cancer Center. Hahn was named deputy president and chief operating officer in 2017. In that role, he was responsible for the day-to-day operations of the cancer center, which includes managing more than 21,000 employees and a $5.2 billion operating budget. He was promoted to that position two years after joining MD Anderson as division head, department chair and professor of Radiation Oncology. Prior to MD Anderson, Hahn served as head of the radiation oncology department at the University of Pennsylvania’s Perelman School of Medicine.

Flagship Founder and Chief Executive Officer Noubar Afeyan said the COVID-19 pandemic that shut down economies and caused the deaths of more than 3.8 million people across the world was an important reminder that health security is a top global priority. In addition, the ongoing pandemic brings into “stark focus” the importance of preemptive medications. 

Hahn, who helmed the FDA for three years and before that served as chief medical executive at The University of Texas MD Anderson Cancer Center, has extensive experience overseeing clinical and administrative programs. Afeyan said the new division would benefit from Hahn’s experience as FDA Commissioner and help steer the Preemptive Medicine and Health Security initiative as it explores Flagship’s “growing number of explorations and companies in this emerging field.”

It is not unusual for former FDA heads to take prominent roles with companies. For example, former FDA Commissioner Scott Gottlieb, Trump’s first FDA Commissioner, took a position on the Pfizer Board of Directors weeks after departing his government role. He has also taken positions on other boards since then, including Aetion, FasterCures and Illumina.

 

BioSpace source:

https://www.biospace.com/article/former-fda-head-stephen-hahn-takes-cmo-role-at-flagship-pioneering-preemptive-health-initiative-

 

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Government

Five U.S. states had coronavirus infections even before first reported cases – study

At least seven people in five U.S. states were infected with the novel coronavirus weeks before those states reported their first cases, a new government study showed.

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Five U.S. states had coronavirus infections even before first reported cases – study

(Reuters) – At least seven people in five U.S. states were infected with the novel coronavirus weeks before those states reported their first cases, a new government study showed.

Participants who reported antibodies against SARS-CoV-2 were likely exposed to the virus at least several weeks before their sample was taken, as the antibodies do not appear until about two weeks after a person has been infected, the researchers said.

The latest results build on findings from a Centers for Disease Control and Prevention study that suggested the novel coronavirus may have been circulating in the United States last December, well before the first COVID-19 case was diagnosed on Jan. 19, 2020.

A protective face mask lays, as the global outbreak of the coronavirus disease (COVID-19) continues, beside leaves at the lakefront in Chicago, Illinois, U.S., December 6, 2020. REUTERS/Shannon/File Photo

The positive samples came from Illinois, Massachusetts, Mississippi, Pennsylvania and Wisconsin, and were part of a study of more than 24,000 blood samples taken for a National Institutes of Health research program between Jan. 2 and March 18, 2020.

Samples from participants in Illinois were collected on Jan. 7 and Massachusetts on Jan. 8, suggesting that the virus was present in those states as early as late December.

“This study allows us to uncover more information about the beginning of the U.S. epidemic,” said Josh Denny, one of the study authors.

The findings were published in the journal Clinical Infectious Diseases.

Reporting by Mrinalika Roy in Bengaluru; Editing by Anil D’Silva

Our Standards: The Thomson Reuters Trust Principles.

 

Reuters source:

https://www.reuters.com/business/healthcare-pharmaceuticals/five-us-states-had-coronavirus-infections-even-before-first-reported-cases-study-2021-06-15

 

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